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| Name | Class |
|---|---|
| United States Department of Defense | FED |
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The clinical trial is intended to assess for clinical evidence of Clemastine Fumarate as a myelin repair therapy in patients with chronic inflammatory injury-causing demyelination as measured by multi-parametric MRI assessments.
No reparative therapies exist for the treatment of multiple sclerosis. Clemastine fumarate was identified along with a series of other antimuscarinic medications as a potential remyelinating agent using the micropillar screen (BIMA) developed at the University of California, San Francisco (UCSF). Following in vivo validation, an FDA IND exemption was granted to investigate clemastine for the treatment of multiple sclerosis in the context of chronic optic neuropathy. That pilot study was recently completed and is the first randomized control trial documenting efficacy for a putative remyelinating agent for the treatment of MS. The preselected primary efficacy endpoint (visual evoked potential) was met and a strong trend to benefit was seen for the principal secondary endpoint assessing function (low contrast visual acuity). That trial number was 13-11577.
This study seeks to follow up on that study and examine clemastine fumarate's protective and reparative effects in the context of chronic demyelinating brain lesions as imaged by multi-parametric MRI assessments. The investigators will be assessing the effects of clemastine fumarate as a remyelinating therapy and assessing its effect on MRI metrics of chronic lesions found in patients with a confirmed diagnosis of relapsing-remitting multiple sclerosis.
In addition to using conventional multi-parametric MRI assessments, this study will also evaluate a new MRI technique called Ultrashort Echo Time (UTE) MRI to assess the effects of clemastine fumarate as a remyelinating therapy of chronic lesions found in patients with a confirmed diagnosis of relapsing-remitting multiple sclerosis and compare it to the other assessments.
Treatments capable of remyelination are a major unmet need for multiple sclerosis and other diseases that involve myelin damage, loss, or dysfunction in the central nervous system (CNS). Chronic demyelination of axons is believed to be injurious to neurons and serves as a major contributor to irreversible cell loss that underlies permanent disability. Available MS treatments are primarily immunosuppressing, without directly addressing or fully preventing axonal degeneration and disability. Clemastine fumarate was identified along with a series of other antimuscarinic medications as a potential remyelinating agent using the micropillar screen (BIMA) developed at UCSF. The screen demonstrated that clemastine promoted the differentiation of the endogenous oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes. Following in vivo validation, an FDA investigational new drug (IND) exemption was granted to investigate clemastine for the treatment of multiple sclerosis in the context of chronic optic neuropathy. That pilot study was recently completed and is the first randomized control trial documenting efficacy for a putative remyelinating agent for the treatment of MS. The preselected primary efficacy endpoint (visual evoked potential) was met and a strong trend to benefit was seen for the principal secondary endpoint assessing function (low contrast visual acuity). That trial number was 13-11577.
This clinical trial is intended to assess magnetic resonance imaging evidence of remyelination using Clemastine Fumarate in patients with chronic demyelinated lesions. Specifically speaking, the primary objective will assess various multi-parametric MRI sequences on the corpus callosum region, a region that animal models studies identified as a promising candidate for assessing remyelination. The aim was to help define the potential for MRI in measuring remyelination in MS, determine the optimal sequences and location for measuring myelin recovery, and help guide trial design for future remyelinating trials. Finally, the study is designed to assess tolerability and clinical efficacy of Clemastine using outcomes intended to assess for (a) adverse events and (b) recovery of myelin.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Clemastine 8 mg, then Placebo | Experimental | Group 1 will receive the treatment (clemastine 8mg/day) for the first 90 days and then switch to the placebo (a sugar pill) for the remaining 90 days |
|
| Placebo, then Clemastine 8 mg | Experimental | Group 2 will receive the placebo (a sugar pill) for the first 90 days and then switch to the treatment (clemastine 8mg/day) for the remaining 90 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clemastine Fumarate | Drug | 8 mg Clemastine tablet. Clemastine fumarate was approved by the Food and Drug Administration (FDA) for the treatment of allergic rhinitis (seasonal allergies) in 1977 and was approved for over-the-counter marketing in 1992. Clemastine is not FDA approved as a remyelinating therapy |
| Measure | Description | Time Frame |
|---|---|---|
| Corpus Callosum Myelin Water Fraction | The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. | This will be assessed at the baseline visit. |
| Change from Baseline in Corpus Callosum Myelin Water Fraction at 3 Months | The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Corpus Callosum Myelin Water Fraction at 6 Months | The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Corpus Callosum T1 Relaxation Time | The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. | This will be assessed at the baseline visit. |
| Change from Baseline in Corpus Callosum T1 Relaxation Time at 3 Months | The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. Change = (3-month time - Baseline time) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Corpus Callosum T1 Relaxation Time at 6 Months |
| Measure | Description | Time Frame |
|---|---|---|
| Optic Radiation Myelin Water Fraction | The efficacy of Clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. | This will be assessed at the baseline visit. |
| Change from Baseline in Optic Radiation Myelin Water Fraction at 3 Months |
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Inclusion Criteria:
Written informed consent must be obtained prior to any assessment being performed.
Patients diagnosed with relapsing remitting multiple sclerosis and a disease duration of < 15 years
Male or female patients aged 18-55 years (inclusive)
Use of appropriate contraception during period of trial (women). Before entry women must be:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Harkeerat Halait, BS | Contact | 415-745-1304 | Harkeerat.Halait@ucsf.edu | |
| Angelica Montevirgen | Contact | 415-745-1304 | Angelica.Montevirgen@ucsf.edu |
| Name | Affiliation | Role |
|---|---|---|
| Ari J Green, MD, MCR | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sandler Neurosciences Building, Neurological Clinical Research Unit | Recruiting | San Francisco | California | 94107 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24997607 | Background | Mei F, Fancy SPJ, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJM, Green A, Hauser SL, Chan JR. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014 Aug;20(8):954-960. doi: 10.1038/nm.3618. Epub 2014 Jul 6. | |
| 19819338 |
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This is a 6-month randomized double-blinded, placebo-controlled, delayed treatment study examining clemastine fumarate as a remyelinating agent in participants with multiple sclerosis. This trial will include n = 74 patients with a confirmed diagnosis of relapsing-remitting multiple sclerosis.
Patients who fulfill the enrollment criteria will be randomly assigned (1:1) via block randomization using a random number generator to receive either clemastine for 90 days followed by placebo for 90 days (Clemastine 8 mg, then Placebo) or placebo for 90 days followed by clemastine for 90 days (Placebo, then Clemastine 8 mg).
If they are on one, patients will be permitted to remain on their standard disease-modifying treatment during the course of the study. These therapies have no identified effect on remyelination.
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|
| Placebo | Drug | Matched sugar tablet |
|
|
The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. Change = (6-month time - Baseline time) |
| This will be assessed at the baseline and 6-month visits. |
| Corpus Callosum UTE Fraction | The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum. | This will be assessed at the baseline visit. |
| Change from Baseline in Corpus Callosum UTE Fraction at 3 Months | The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Corpus Callosum UTE Fraction at 6 Months | The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. Change = (3-month % - Baseline %) |
| This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Optic Radiation Myelin Water Fraction at 6 Months | The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Corticospinal Tract Myelin Water Fraction | The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. | This will be assessed at the baseline visit. |
| Change from Baseline in Corticospinal Tract Myelin Water Fraction at 3 Months | The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Corticospinal Tract Myelin Water Fraction at 6 Months | The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Optic Radiation T1 Relaxation time | To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. | This will be assessed at the baseline visit. |
| Change from Baseline in Optic Radiation T1 Relaxation Time at 3 Months | To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. Change = (3-month time - Baseline time) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Optic Radiation T1 Relaxation Time at 6 Months | To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Corticospinal Tract T1 Relaxation Time | To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. | This will be assessed at the baseline visit. |
| Change from Baseline in Corticospinal T1 Relaxation Time at 3 Months | To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. Change = (3-month time - Baseline time) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Corticospinal Tract T1 Relaxation Time at 6 Months | To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Optic radiation UTE Fraction | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. | This will be assessed at the baseline visit. |
| Change from Baseline in Optic radiation UTE Fraction at 3 Months | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Optic radiation UTE Fraction at 6 Months | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Corticospinal Tract UTE Fraction | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. | This will be assessed at the baseline visit. |
| Change from Baseline in Corticospinal Tract UTE Fraction at 3 Months | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Corticospinal Tract UTE Fraction at 6 Months | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Lesion of interest (LOI) MWF | The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. | This will be assessed at the baseline visit. |
| Change from Baseline in LOI MWF at 3 Months | The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in LOI MWF at 6 Months | The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| LOI T1 Relaxation Time | The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. | This will be assessed at the baseline visit. |
| Change from Baseline in LOI T1 Relaxation Time at 3 Months | The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month time - Baseline time) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in LOI T1 Relaxation Time at 6 Months | The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (6-month time - Baseline time) | This will be assessed at the baseline and 6-month visits. |
| LOI UTE Fraction | The efficacy of clemastine relative to placebo at increasing UTE fraction (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. | This will be assessed at the baseline visit. |
| Change from Baseline in LOI UTE Fraction at 3 Months | The efficacy of clemastine relative to placebo at increasing UTE fraction (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in LOI UTE Fraction at 6 Months | The efficacy of clemastine relative to placebo at increasing UTE fraction (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Whole Brain MWF | The efficacy of clemastine relative to placebo at increasing MWF (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. | This will be assessed at the baseline visit. |
| Change from Baseline in Whole Brain MWF at 3 Months | The efficacy of clemastine relative to placebo at increasing MWF (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Whole Brain MWF at 6 Months | The efficacy of clemastine relative to placebo at increasing MWF (measured in %) values across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Whole Brain T1 Relaxation Time | The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. | This will be assessed at the baseline visit. |
| Change from Baseline in Whole Brain T1 Relaxation Time at 3 Months | The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (3-month time - Baseline time) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Whole Brain T1 Relaxation Time at 6 Months | The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (6-month time - Baseline time) | This will be assessed at the baseline and 6-month visits. |
| Whole Brain UTE Fraction | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. | This will be assessed at the baseline visit. |
| Change from Baseline in Whole Brain UTE Values at 3 Months | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (3-month % - Baseline %) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Whole Brain UTE Values at 6 Months | The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (6-month % - Baseline %) | This will be assessed at the baseline and 6-month visits. |
| Clemastine Tolerability | The tolerability of Clemastine in this population. This will include a special focus with regards to fatigue as this is a major symptom for patients suffering from multiple sclerosis. | This will be assessed at the baseline visit. |
| Change from Baseline in Clemastine Tolerability at 3 Months | The tolerability of Clemastine in this population. This will include a special focus with regards to fatigue as this is a major symptom for patients suffering from multiple sclerosis. Change = (3-month tolerability - Baseline tolerability) | This will be assessed at the baseline and 3-month visits. |
| Change from Baseline in Clemastine Tolerability at 6 Months | The tolerability of Clemastine in this population. This will include a special focus with regards to fatigue as this is a major symptom for patients suffering from multiple sclerosis. Change = (6-month tolerability - Baseline tolerability) | This will be assessed at the baseline and 6-month visits. |
| Informative Outcomes | Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications). | This will be assessed at the baseline visit. |
| Informative Outcomes at 3 Months | Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications). | This will be assessed at the 3-month visit. |
| Informative Outcomes at 6 Months | Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications). | This will be assessed at the 6-month visit. |
| Marques JP, Kober T, Krueger G, van der Zwaag W, Van de Moortele PF, Gruetter R. MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field. Neuroimage. 2010 Jan 15;49(2):1271-81. doi: 10.1016/j.neuroimage.2009.10.002. Epub 2009 Oct 9. |
| 27155128 | Background | Sheth V, Shao H, Chen J, Vandenberg S, Corey-Bloom J, Bydder GM, Du J. Magnetic resonance imaging of myelin using ultrashort Echo time (UTE) pulse sequences: Phantom, specimen, volunteer and multiple sclerosis patient studies. Neuroimage. 2016 Aug 1;136:37-44. doi: 10.1016/j.neuroimage.2016.05.012. Epub 2016 May 5. |
| 29029896 | Background | Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Budingen HC, Henry RG, Hauser SL, Chan JR. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017 Dec 2;390(10111):2481-2489. doi: 10.1016/S0140-6736(17)32346-2. Epub 2017 Oct 10. |
| 17308868 | Background | Gagliardo A, Galli F, Grippo A, Amantini A, Martinelli C, Amato MP, Borsini W. Motor evoked potentials in multiple sclerosis patients without walking limitation: amplitude vs. conduction time abnormalities. J Neurol. 2007 Feb;254(2):220-7. doi: 10.1007/s00415-006-0334-5. Epub 2007 Feb 17. |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D020529 | Multiple Sclerosis, Relapsing-Remitting |
| D020528 | Multiple Sclerosis, Chronic Progressive |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D002974 | Clemastine |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D002241 | Carbohydrates |
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